The blood vessels, together with the heart and the lymph vessels, constitute a vasculature which is indispensable for sustained metabolism of tissues and, hence, functional homeostasis of an organism. The chief constituent cells of a blood vessel are endothelial cells and smooth muscle cells. Proliferation of endothelial cells in the established vascular system is usually observed in the neovascularization process giving rise to a new network of capillary blood vessels chiefly from venules and the repair process following exfoliation of vascular endothelial cells. As it has recently been made clear that neovascularization is closely involved in pathology of growth of solid tumors, arteriosclerosis, hyperplasia of panni in rheumatoid arthritis, ophthalmic diseases such as diabetic proliferative retinopathy, psoriasis vulgaris, etc., there is a mounting interest in neovascularization.
The mechanism of neovascularization in cancers, rheumatoid arthritis, diabetic retinopathy, etc. is known to begin with a disruption of extracellular matrix which triggers migration of endothelial cells to form a tube which, in turn, is followed by the migration and proliferation of vascular smooth muscle cells around the tube to complete a new blood vessel.
Several compounds (e.g. D-penicillamine, heparin, 15-deoxyspergaulin, eponemycin AGM-1470, tecogalan sodium (DS-4152), herbimycin A, and interferon-alpha) are known to inhibit neovascularization. Those compounds are either biological component-related substances or substances of the natural origin and, therefore, the source of their supply is too limited for practical utilization.
The antitumor agent irsogladine maleate 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine maleate!, which is structurally close to the compound of the invention, reportedly inhibits neovascularization (FEBS, 322(2), 155-158, 1993). However, the 2-amino-4-substituted amino-6-(2,5-dichlorophenyl)-1,3,5-triazine derivative which is theoretically available upon substitution of one of the amino groups by alkyl, aralkyl, arylalkenyl, or aryl is not known to have neovascularization inhibitory activity.
Meanwhile, the inventors of the present invention previously discovered that the 2-amino-4-substituted amino-6-(2,5-dichlorophenyl)-1,3,5-triazine derivative has antihepatitis activity and is useful as a therapeutic agent for hepatitis and already filed a patent application (WO 96/04914).